Artificial induction of tolerance to self or to foreign antigens is the goal of therapy for autoimmunity, transplantation allergy and other diseases, and is also desirable in the context of therapy with autologous proteins and non-autologous proteins. Until recently, therapeutic tolerance induction relied on broad-based approaches that resulted in cellular depletion and cytokine profile alteration. These broad-based approaches weaken the immune system in general and leave many subjects vulnerable to opportunistic infections, autoimmune attack and cancer. There is a need in the art for less aggressive and more targeted approaches to the induction of immune tolerance.
Immune tolerance is regulated by a complex interplay between T cells, B cells, cytokines and surface receptors. Initial self/non-self discrimination occurs in the thymus during neonatal development where medullary epithelial cells express specific self protein epitopes to immature T cells. T cells recognizing self antigens with high affinity are deleted, but autoreactive T cells with moderate affinity sometimes avoid deletion and can be converted to so called ‘natural’ regulatory T cells (Treg) cells. These natural Treg cells are exported to the periphery and provide for constant suppression of autoimmunity.
A second form of tolerance occurs in the periphery where mature T cells are converted to an ‘adaptive’ Treg phenotype upon activation via their T cell receptor in the presence of IL-10 and TGF-.beta. The possible roles for these ‘adaptive’ Treg cells include dampening immune response following the successful clearance of an invading pathogen as a means of controlling excessive inflammation as might be caused by an allergic reaction or low level chronic infection, or possibly to facilitate co-existence with beneficial symbiotic bacteria and viruses. ‘Adaptive’ Treg may also play a role in managing the life cycle of human antibodies that have undergone somatic hypermutation.
Natural regulatory T cells are a critical component of immune regulation in the periphery. Upon activation through their TCR natural Tregs are capable of suppressing bystander effector T cell responses to unrelated antigens through contact dependent and independent mechanisms. In addition the cytokines released by these cells including IL-10 and TGF-.beta., are capable of inducing antigen-specific adaptive Tregs. Despite extensive efforts, with few exceptions, the antigen specificity of natural Tregs, and more importantly natural Treg circulating in clinically significant volumes, is still unknown.
There is need in the art for the identification of new regulatory T cell epitopes contained in common autologous proteins such as IgG (“Tregitopes”) and for methods for related to their preparation and of use.
Chronic hepatitis C virus (HCV) infection is a major public health concern worldwide. It is the leading cause of liver failure and reason for liver transplant in the US. Irrespective of clinical outcome, acute HCV infections are characterized by broad HCV-specific T cell responses that correlate with spontaneous viral clearance in a minority of individuals. In most patients, however, this initial response fails to contain the virus and chronic disease results. Increased numbers of CD4+ regulatory T(reg) cells circulating in the bloodstream and accumulating in the liver have been implicated in the pathogenesis of chronic hepatitis C.
Treg cells constitute one of the major mechanisms underlying immunological homeostasis and self-tolerance. In addition, Treg cells play a key role in moderating the immune response to infectious diseases, suppressing host tissue and organ damage that would occur in the absence of regulation. Although key to maintaining immune homeostasis, a growing body of evidence suggests that Treg cells also contribute to the establishment and persistence of chronic infections, e.g., HCV. While no single marker exists, human Treg cells are classically identified by expression of the transcription factor, forkhead box P3 (FoxP3), and the cell surface expression of the interleukin (IL)-2 receptor a chain (CD25). Bystander suppression is an additional key feature of Treg cells.
Two distinct Treg cell subsets are described in the literature: natural (n)Treg cells specific for self epitopes and generated by high-avidity selection in the thymus, and inducible (i)Treg cells that derive from conventional (CD4+CD25−FoxP3−) T cells following stimulation in the periphery. nTreg cells can induce the conversion of conventional T cells to iTreg cells via cytokine-dependent and -independent mechanisms, a process called infectious tolerance. Notably, the factors that affect expansion of the Treg cell population in cases of chronic hepatitis C remain to be fully delineated. Nonetheless, the consensus supports the heterogeneous nature of the expanded Treg cell population composed of both nTreg and iTreg cell subsets.